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Abstract

Aim: Atherosclerosis, characterized by neointima formation, occurs preferentially at areas of disturbed flow. Extracellular matrix protein CCN1 is upregulated at the site of atherosclerotic lesions in humans and in animal models. Our aim was to examine the expression of CCN1-regulated by disturbed flow and its role in neointima formation.

Methods and Results: Ccn1+/lacZ mice, in which a lacZ reporter gene was inserted to be driven by Ccn1-promoter, were subjected to complete ligation of the left common carotid artery. Progressive reduction in luminal diameters of the ligated artery were observed using B mode ultrasound compared with the right common carotid artery. Ccn1 expression, assessed by whole-mount X-gal staining, was detected in the intima and the media of carotid arteries 3 days after ligation, and the staining intensified between 1-4 weeks in the neointima after ligation. Specifically, Ccn1 expression was observed in endothelial cells, smooth muscle cells, and macrophages in the neointima. To dissect the role of CCN1 in the development of arterial lesions, knock-in mice carrying the integrin α6β1-binding-deficient mutant allele Ccn1-dm were tested in the carotid artery ligation model. Compared with wild-type mice, Ccn1dm/dm mice displayed significantly less neointima after ligation with improved endothelial function, less endothelial apoptosis, and lower oxidative stress, suggesting that the arterial expression of CCN1 induces endothelial dysfunction through its receptor integrin α6β1.